Prescription opioid abuse affects 2.4 million Americans and poses a societal burden of $55.7 billion annually. These prescription opioids are primarily ?-opioid receptor (MOR) agonists, and are not only highly addictive but their deadly side effects have caused more overdose deaths than heroin and cocaine combined. Therefore, research to identify analgesics that lack the potential for abuse and severe side effects associated with MOR agonists are urgently needed. Recent studies indicate that targeting the nociceptin receptor (NOP) is a promising alternative route to relieving pain without the deleterious side effects of traditional MOR-activating opioid therapies. In non-human primates, specifically activating NOP induces long lasting, morphine-comparable analgesia without causing pruritus, respiratory depression, or reinforcing effects in an intravenous self-administration paradigm; thus eliminating three serious side-effects of current opioid therapies. Our goal is to develop a mechanistic understanding of NOP signaling through intensive structural studies of NOP and leveraging our newfound understanding of this critical drug target to develop a predictive model for the action of different NOP ligand chemotypes. This goal will be accomplished through the following specific aims: (1) Determine and analyze the three-dimensional molecular structure of activated NOP (2) Delineate the activation mechanism of constitutively active mutants of NOP and finally (3) Define the structure of agonist- bound NOP in complex with effector fragments. The structural and functional data generated throughout this project will be combined and leveraged in computational studies to extend our newfound understanding of NOP activation to the identification of new NOP-activating chemotypes. This potentially high-impact project would pave the way for the development of the next generation of analgesics that lack the abuse liability and serious side effects associated with current opioid therapies.